Every year, millions of infants and children undergo surgery under general anesthesia in the world. Sevoflurane is a commonly used pediatric anesthetic. Its exposure during brain development has been shown to inhibit neurogenesis and cause cognitive dysfunction in animal models. Nevertheless, the underlying mechanisms remain elusive. Normal neurogenesis constitutes the neurobiological foundation for higher-order brain functions, such as learning and memory. Lipid metabolism is crucial for the regulation of neurogenesis.
"Carnitine palmitoyltransferase 1a (CPT1a) is a key molecule in regulating fatty acid β-oxidation (FAO), and PPARα serves as the principal regulatory factor of CPT1a. However, the potential alterations in FAO mediated by the peroxisome proliferator-activated receptor α (PPARα)/CPT1a pathway in neural stem/progenitor cells (NSPCs) following sevoflurane exposure, and its potential role in sevoflurane-induced neurogenesis inhibition and cognitive dysfunction, remain unclear.
Methods
NSPCs, NE-4C cells, and postnatal day 7 rats were exposed to 3% sevoflurane for 6 hours. Immunohistochemistry was used to verify whether sevoflurane exposure inhibits neurogenesis. The Morris water maze was employed to explore whether sevoflurane exposure impairs cognitive function. Untargeted lipidomics, FAOBlue staining, RNA isolation and real-time reverse transcription polymerase chain reaction (RT-qPCR), western blotting, CPT1a enzyme activity assay, and immunohistochemistry were utilized to validate the impact of sevoflurane exposure on FAO in NSPCs. Octanoate pretreatment, CPT1a overexpression, PPARα agonist palmitoylethanolamide (PEA), and FAO substrate carnitine pretreatment were collectively employed to reveal the role of FAO and PPARα in NSPCs on sevoflurane-induced neurogenesis inhibition and cognitive impairment.
Sevoflurane exposure inhibited neurogenesis and impaired cognitive function. In NSPCs, sevoflurane exposure caused extensive changes in lipid metabolism intermediates, inhibited the mRNA expression of acyl-CoA oxidase 1 (ACOX1), acyl-CoA oxidase 3 (ACOX3), hydroxyacyl-CoA dehydrogenase beta subunit (HADHB), CPT1a, carnitine palmitoyltransferase 2 (CPT2), acyl-CoA dehydrogenase short-chain (ACADS), and solute carrier family 22 member 5 (SLC22A5), suppressed FAO activity, and decreased the protein expression and activity of CPT1a. Enhancing FAO activity in NSPCs attenuated sevoflurane-induced neurogenesis impairment. Overexpression of CPT1a rescued sevoflurane-induced inhibition of FAO activity and neurogenesis in NE-4C cells. Besides, sevoflurane exposure reduced the expression levels of PPARα in the nuclei of NSPCs and hippocampal tissue. Pretreatment with PEA increased the nuclear content of PPARα and the expression of CPT1a in NSPCs and the rat hippocampus after sevoflurane exposure. Moreover, pretreatment with PEA or the CPT1a substrate carnitine rescued the sevoflurane-induced decrease of FAO activity in NSPCs, inhibition of neurogenesis in vivo and in vitro, and the cognitive impairment.
Discussion
Previous work has not investigated whether or how FAO participates in sevoflurane-induced neurogenesis inhibition and cognitive decline. Our study showed that sevoflurane inhibited neurogenesis and impaired cognitive function likely by inhibiting FAO in NSPCs through the PPARα/CPT1a pathway.This study reveals a new potential mechanism of sevoflurane neurodevelopmental toxicity. Future research is needed to clarify the role of FAO in NSPCs in sevoflurane-induced neurogenesis inhibition and cognitive impairment, and to explore the mechanisms that execute this FAO-dependent effect.
Reference
DOI: 10.1097/CM9.0000000000003864
About Xi'an Jiaotong University
The Second Affiliated Hospital of Xi'an Jiaotong University (Northwest Hospital), also known as the Second School of Clinical Medicine of Xi'an Jiaotong University, is a large-scale comprehensive hospital directly governed by Ministry of Education and National Health Commission. As a Class III Grade A hospital—the highest national accreditation for medical institutions in China—it integrates clinical services, education, research, rehabilitation, and preventive care.
Historical Legacy
Founded in 1912 as part of Beijing Medical School, the first national higher medical college in China, and later evolving from the affiliated hospital of Peking University Medical College, the institution was relocated to Shaanxi Province in 1937 during the War of Resistance against Japan. This move preserved China's higher medical education amid national crisis and established the region's first university-affiliated hospital, laying the groundwork for modern clinical medicine and medical education in northwest China.
Scale and Capacity
The hospital operates 2,583 inpatient beds, serving over 2.6 million outpatient and emergency visits annually, with more than 130,000 hospital admissions. It employs 4,385 staff members, including over 600 experts with deputy senior or higher professional titles. More than 50 experts receive special allowances from the State Council, and the hospital has 288 scholars holding standing committee positions or higher in provincial medical associations, over 100 leaders in national/international academic societies, and 106 editorial board members of major national journals.
Disciplinary Excellence
With two campuses, eight specialized disease centers, six clinical/research hubs, and 63 clinical/medical technology departments, the hospital offers comprehensive medical disciplines. It is a national project unit for improving diagnosis/treatment of complex diseases, a national regional medical center (focus: Respiratory and Critical Care Medicine), and a pilot "Flagship Hospital" for integrating traditional Chinese and Western medicine. Key institutions include a Ministry of Education Key Laboratory, a National Local Joint Engineering Research Center for Biotherapy, a National Complex Disease Diagnosis-Treatment Center (Respiratory and Critical Care Medicine), China's first Medical Artificial Intelligence Research Institute within a medical institution, and the nation's first National Engineering Laboratory for Big Data Algorithms and Analysis. It hosts 24 National Key Clinical Specialties, 2 national key disciplines, 16 Shaanxi Provincial Key Clinical Specialties, and 7 provincial medical quality control centers.
Medical Innovations
The hospital has pioneered numerous global/national firsts:
World's first fully thoracoscopic closure of tracheoesophageal fistula using 3D-printed biodegradable materials
World's first fluorescent imaging-assisted resection of pediatric teratoma
World's first rechargeable dual-electrode sacral neuromodulation surgery
China's first successful treatment of Kimura disease and gestational pemphigoid with dupilumab
Landmark procedures like ex vivo liver resection with autologous liver transplantation (the most complex in liver transplantation) and Shaanxi's first 5G remote robotic prostatectomy.
Education and Training
As one of China's first National Clinical Teaching and Training Demonstration Centers, it manages 19 academic departments and 1 teaching division, offering education at postdoctoral, doctoral, master's, undergraduate, and international student levels. It leads national continuing medical education programs and Shaanxi's general practitioner training, having educated tens of thousands of medical professionals globally. As a national standardized training base for resident/specialist physicians, it has authored national medical textbooks and won dozens of national/provincial teaching awards. Faculty members have recently earned top prizes in competitions like the National University Young Teachers Competition and the National Teaching Innovation Competition.
Research Achievements
Annually, the hospital secures over 100 research grants, including those from the National Natural Science Foundation of China. Since 2000, it has published 50 high-impact academic works, won 15 provincial/national science and technology awards (4 first prizes), and obtained 260 patents. Annual SCI-indexed publications have grown steadily, highlighted by a 2020 Science journal publication with an impact factor of 44.002.
Academic Journals
Three journals managed by the hospital—Chinese Journal of Dermatology and Venereology, Chinese Journal of Child Health Care, and Dermatology Bulletin—are indexed in the Chinese Science Citation Database (CSCD) and major international databases (U.S., UK, Russia, Sweden, Japan).
Medical Technology
State-of-the-art equipment includes a 5T MRI, Da Vinci surgical robots, PET-CT, high-end linear accelerators, and mobile units like a bus-mounted CT and mobile P2 laboratory. These assets enhance both daily care and emergency response capabilities during public health crises.
Social Commitment
As a national regional medical center, the hospital partners with nearly 100 grassroots hospitals through trusteeship, medical consortia, and collaborative networks. It leads rural medical support, targeted assistance, and national emergency missions, including aid to Tibet, Xinjiang, and African nations like Sudan and Malawi. Recognized for its role in disaster relief and pandemic control (e.g., COVID-19), it has received honors such as "National Civilized Unit" and "Shaanxi Advanced Collective in COVID-19 Response." Staff accolades include the Florence Nightingale Medal, Bethune Medal, National May Day Labor Medal, and "Most Beautiful Doctor" by China's Ministry of Publicity and National Health Commission.
Future Vision
To address rising healthcare demands, the hospital is expanding its "one hospital, multiple campuses" model. New branches in Luoyang and Xinjiang—part of the national regional medical center initiative—ensure standardized, high-quality care across locations. Guided by the "Xi'an Relocation Spirit"—a legacy of selfless dedication and resilience from the 1950s westward migration of intellectuals—and its motto, "Benevolent Hearts, Skillful Hands, Virtue, and Innovation; Truth-Seeking, Dedication, and Pioneering", the hospital remains committed to advancing public health and contributing to China's healthcare goals.
Website: http://www.2yuan.xjtu.edu.cn/
About Professor Pengbo Zhang from Xi'an Jiaotong University
Pengbo Zhang is a Chief Physician, Professor, and Doctoral Supervisor at The Second Affiliated Hospital of Xi'an Jiaotong University. With over 30 years of experience since graduating from Xi'an Medical University in 1992, he has published more than 80 academic papers. His research focuses on perioperative brain protection and neural injury repair. Recognized for his contributions, he was selected for the Ministry of Education's "New Century Excellent Talents" program in 2008 and received the Shaanxi Provincial Science and Technology Award.
About Professor Haidong Wei from Xi'an Jiaotong University
Dr. Haidong Wei, MD, is Deputy Director of Anesthesiology at Xi'an Jiaotong University's Second Affiliated Hospital. With extensive clinical experience, his research focuses on perioperative brain injury and cerebral energy metabolism, particularly astrocytic lipid metabolism in neural repair. He has published in journals including Journal of Neuroinflammation and International Journal of Biological Sciences, and leads National Natural Science Foundation projects, receiving the Shaanxi Youth Science and Technology Award.
Funding information
This study was supported by the National Natural Science Foundation of China (Grant Nos. 82220108011 and 82071482) and the National Key Research and Development Program of China (Grant No. 2019YFE0115300).
